The present invention relates to an improved method for cell line development which is generally applicable to production of any therapeutic protein that can be produced using mammalian Cell lines and in particular Chinese Hamster Ovary (CHO) cells. The method combines site directed integration (SDI), expression construct components improving the post-transcriptional processing of the gene of interest (GOI), novel design of the GO genome target location and the introduction of a onetime pre-CLD host cell line selection workflow to generate a production competent cell line that can then be used in multiple CLD efforts from that point on.